Publications by authors named "Xianling Feng"

17 Publications

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MiRNA-20b/SUFU/Wnt axis accelerates gastric cancer cell proliferation, migration and EMT.

Heliyon 2021 Apr 12;7(4):e06695. Epub 2021 Apr 12.

Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China.

Previous research has found that miRNA-20b is highly expressed in gastric cancer (GC), however, its function and underlying mechanism are not clear. Wnt signaling pathway, implicated in tumorigeneisis, is activated in more than 30% of GC. We would like to characterize the biological behavior of miRNA-20b in terms of modulating Wnt/β-catenin signaling and EMT. We showed that miRNA-20b inhibitors suppressed Topflash/Fopflash dependent luciferase activity and the β-catenin nuclear translocation, resulting in inhibition of Wnt pathway activity and EMT. SUFU, negatively regulating Wnt and Hedgehog signaling pathway, was proved to be targeted by miRNA-20b. Moreover, additional knockdown of SUFU alleviated the inhibitory effect on Wnt pathway activity, EMT, cell proliferation/migration and colony formation caused by miRNA-20b inhibition. In summary, miRNA-20b is an oncogenic miRNA and promoted cell proliferation, migration and EMT in GC partially by activating Wnt pathway via targeting SUFU.
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http://dx.doi.org/10.1016/j.heliyon.2021.e06695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065298PMC
April 2021

Dual activation of Hedgehog and Wnt/β-catenin signaling pathway caused by downregulation of SUFU targeted by miRNA-150 in human gastric cancer.

Aging (Albany NY) 2021 Apr 12;13(7):10749-10769. Epub 2021 Apr 12.

Guangdong Key Laboratory for Genome Stability and Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen 518060, Guangdong, P.R. China.

Mounting evidence has shown that miRNA-150 expression is upregulated in gastric cancer (GC) and is associated with gastric carcinogenesis, but the underlying oncogenic mechanism remains elusive. Here, we discovered that miRNA-150 targets the tumor suppressor SUFU to promote cell proliferation, migration, and the epithelial-mesenchymal transition (EMT) via the dual activation of Hedgehog (Hh) and Wnt signaling. MiRNA-150 was highly expressed in GC tissues and cell lines, and the level of this miRNA was negatively related to that of SUFU. In addition, both the miRNA-150 and SUFU levels were associated with tumor differentiation. Furthermore, miRNA-150 activated GC cell proliferation and migration . We found that miRNA-150 inhibitors repressed not only Wnt signaling by promoting cytoplasmic β-catenin localization, but also repressed Hh signaling and EMT. MiRNA-150 inhibition also resulted in significant tumor volume reductions , suggesting the potential application of miRNA-150 inhibitors in GC therapy. The expression of genes downstream of Hh and Wnt signaling was also reduced in tumors treated with miRNA-150 inhibitors. Notably, anti-SUFU siRNAs rescued the inhibitory effects of miRNA-150 inhibitors on Wnt signaling, Hh activation, EMT, cell proliferation, cell migration, and colony formation. Taken together, these findings indicate that miRNA-150 is oncogenic and promotes GC cell proliferation, migration, and EMT by activating Wnt and Hh signaling via the suppression of SUFU expression.
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http://dx.doi.org/10.18632/aging.202895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064165PMC
April 2021

Histone methyltransferase SET8 is regulated by miR-192/215 and induces oncogene-induced senescence via p53-dependent DNA damage in human gastric carcinoma cells.

Cell Death Dis 2020 10 30;11(10):937. Epub 2020 Oct 30.

Guangdong Key Laboratory for Genome Stability & Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, 518060, People's Republic of China.

Gastric cancer (GC) is the most common cancer throughout the world. Despite advances of the treatments, detailed oncogenic mechanisms are largely unknown. In our previous study, we investigated microRNA (miR) expression profiles in human GC using miR microarrays. We found miR-192/215 were upregulated in GC tissues. Then gene microarray was implemented to discover the targets of miR-192/215. We compared the expression profile of BGC823 cells transfected with miR-192/215 inhibitors, and HFE145 cells transfected with miR-192/-215 mimics, respectively. SET8 was identified as a proposed target based on the expression change of more than twofold. SET8 belongs to the SET domain-containing methyltransferase family and specifically catalyzes monomethylation of H4K20me. It is involved in diverse functions in tumorigenesis and metastasis. Therefore, we focused on the contributions of miR-192/215/SET8 axis to the development of GC. In this study, we observe that functionally, SET8 regulated by miR-192/215 is involved in GC-related biological activities. SET8 is also found to trigger oncogene-induced senescence (OIS) in GC in vivo and in vitro, which is dependent on the DDR (DNA damage response) and p53. Our findings reveal that SET8 functions as a negative regulator of metastasis via the OIS-signaling pathway. Taken together, we investigated the functional significance, molecular mechanisms, and clinical impact of miR-192/215/SET8/p53 in GC.
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http://dx.doi.org/10.1038/s41419-020-03130-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599338PMC
October 2020

SUFU mediates EMT and Wnt/β-catenin signaling pathway activation promoted by miRNA-324-5p in human gastric cancer.

Cell Cycle 2020 Oct 5;19(20):2720-2733. Epub 2020 Oct 5.

Guangdong Key Laboratory for Genome Stability & Disease Prevention, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine , Shenzhen, Guangdong, China.

The poor prognosis of late gastric carcinomas (GC) underscores the necessity to identify novel biomarkers for earlier diagnosis and effective therapeutic targets. MiRNA-324-5p has been shown to be over-expressed in GC, however the biological function of miRNA-324-5p implicated in gastric cancer and its downstream targets were not well understood. Wnt/β-catenin signaling pathway is aberrantly regulated in GC. We sought to explore if miRNA-324-5p promotes oncogenesis through modulating Wnt signaling and EMT. MiRNA-324-5p is highly expressed in GC based on qRT-PCR and TCGA data. In addition, in vitro cell proliferation, cell migration assays and in vivo animal exenograft were executed to show that miRNA-324-5p is an oncogenic miRNA in GC. MiRNA-324-5p activates Wnt signaling and induces EMT in GC. Further, SUFU was identified as a target of miRNA-324-5p confirmed by western blotting and luciferase assays. Spearson analysis and TCGA data indicate that the expression of SUFU is negatively associated with the expression of miRNA-324-5p. Rescue experiments were performed to determine if SUFU mediates the Wnt activation, EMT and oncogenic function of miRNA-324-5p. MiRNA-324-5p inhibitors plus SUFU siRNAs rescue partially the inhibitory effect on Wnt signaling and EMT caused by miRNA-324-5p inhibitors. Finally, the suppression of cell proliferation, migration, and colony formation ability induced by miRNA-324-5p inhibitors is alleviated by addition of SUFU siRNAs. In summary, miRNA-324-5p is overexpressed and exerts cell growth and migration-promoting effects through activating Wnt signaling and EMT by targeting SUFU in GC. It represents a potential miRNA with an oncogenic role in human gastric cancer.
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http://dx.doi.org/10.1080/15384101.2020.1826632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644164PMC
October 2020

miRNA-192 and -215 activate Wnt/β-catenin signaling pathway in gastric cancer via APC.

J Cell Physiol 2020 09 24;235(9):6218-6229. Epub 2020 Feb 24.

Department of Pathology, Guangdong Key Laboratory for Genome Stability & Disease Prevention, The Shenzhen University School of Medicine, Shenzhen, Guangdong, China.

Although great progress has been made in surgical techniques, traditional radiotherapy, and chemotherapy, gastric cancer (GC) is still the most common malignant tumor and has a high mortality, which highlights the importance of novel diagnostic markers. Emerging studies suggest that different microRNAs (miRNAs) are involved in tumorigenesis of GC. In this study, we found that miRNA-192 and -215 are significantly upregulated in GC and promote cell proliferation and migration. Adenomatous polyposis coli (APC), a well-known negative regulator in Wnt signaling, has been proved to be a target of miRNA-192 and -215. Inhibition of miRNA-192 or -215 reduced the Topflash activities and repressed the expression of Wnt signaling pathway proteins, while APC small interfering RNAs reversed the inhibitory effects, suggesting that miRNA-192 and -215 activate Wnt signaling via APC. In addition, APC mediates the cell proliferation and migration regulated by miRNA-192 and -215. Furthermore, APC is downregulated in GC tissues and negatively correlated with the expression of miRNA-192 and -215. In summary, miRNA-192 and -215 target APC and function as oncogenic miRNAs by activating Wnt signaling in GC, revealing to be potential therapeutic targets.
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http://dx.doi.org/10.1002/jcp.29550DOI Listing
September 2020

The role of the ERK1/2 pathway in simvastatin-loaded nanomicelles and simvastatin in regulating the osteogenic effect in MG63 cells.

Int J Nanomedicine 2018 5;13:8165-8178. Epub 2018 Dec 5.

Center of Oral Implantology, Guangdong Provincial Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China,

Objectives: The present study aimed to clarify the role of the ERK1/2 pathway in simvastatin (SV)-loaded nanomicelles (SVNs)- and SV-mediated promotion of cell osteogenic differentiation and explore the molecular mechanisms by which SVNs exhibited a greater efficacy in promoting osteogenic differentiation than SV.

Materials And Methods: SVNs were synthesized using a dialysis method. MG63 cells were treated with 2.5, 0.25, and 0.025 μmol/L of the drug. The optimal drug dosage was determined by examining the proliferative activity and ALP activity of the MG63 cells. Subsequently, Western blot analysis was performed to analyze the levels of the phosphorylated ERK1/2 proteins in each experimental group at various time points. Finally, the inhibitor PD98059 was used to effectively inhibit the ERK1/2 pathway. The resulting changes in the proliferative activity of MG63 cells and the osteogenesis-related markers were analyzed.

Results: The SVNs synthesized in the present study had a mean diameter of 27 nm. The encapsulation and drug-loading efficiencies were 52.03% ± 4.05% and 9.42% ± 0.66%, respectively. SVNs and SV exhibited optimum osteogenesis-promoting effects when the drugs were administered at a concentration of 0.25 μmol/L. The drug-induced activation of the ERK1/2 pathway reached a peak at 15 minutes after administration and then declined rapidly. From 24 hours to 7 days, SVNs and SV exerted an inhibitory effect on the ERK1/2 pathway rather than an activating effect. Throughout the whole experimental process, the regulatory effect of SVNs on the ERK1/2 pathway was significantly greater than that of SV. Inhibition of the ERK1/2 pathway by PD98059 markedly reduced the proliferative activity of the cells in all experimental groups. In addition, the ALP activity and the expression levels of the osterix (OSX) and osteocalcin (OC) proteins were drastically increased.

Conclusion: SVNs significantly increased the effect of SV-induced osteogenic differentiation by strongly inhibiting the ERK1/2 pathway.
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http://dx.doi.org/10.2147/IJN.S182998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287536PMC
February 2019

Inhibition of miR‑194 suppresses the Wnt/β‑catenin signalling pathway in gastric cancer.

Oncol Rep 2018 Dec 8;40(6):3323-3334. Epub 2018 Oct 8.

Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, P.R. China.

A mounting body of evidence has revealed that microRNAs (miRs) serve pivotal roles in various developmental processes, and in tumourigenesis, by binding to target genes and subsequently regulating gene expression. Continued activation of the Wnt/β‑catenin signalling is positively associated with human malignancy. In addition, miR‑194 dysregulation has been implicated in gastric cancer (GC); however, the molecular mechanisms underlying the effects of miR‑194 on GC carcinogenesis remain to be elucidated. The present study demonstrated that miR‑194 was upregulated in GC tissues and SUFU negative regulator of Ηedgehog signaling (SUFU) was downregulated in GC cell lines. Subsequently, inhibition of miR‑194 attenuated nuclear accumulation of β‑catenin, which consequently blocked Wnt/β‑catenin signalling. In addition, the cytoplasmic translocation of β‑catenin induced by miR‑194 inhibition was mediated by SUFU. Furthermore, genes associated with the Wnt/β‑catenin signalling pathway were revealed to be downregulated following inhibition of the Wnt signalling pathway by miR‑194 suppression. Finally, the results indicated that cell apoptosis was markedly increased in response to miR‑194 inhibition, strongly suggesting the carcinogenic effects of miR‑194 in GC. Taken together, these findings demonstrated that miR‑194 may promote gastric carcinogenesis through activation of the Wnt/β‑catenin signalling pathway, making it a potential therapeutic target for GC.
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http://dx.doi.org/10.3892/or.2018.6773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196585PMC
December 2018

Inhibition of the miR-192/215-Rab11-FIP2 axis suppresses human gastric cancer progression.

Cell Death Dis 2018 07 13;9(7):778. Epub 2018 Jul 13.

Department of Pathology, School of Basic Medical Sciences, Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen Key Laboratory of Micromolecule Innovatal Drugs, Shenzhen University Health Sciences Center, Shenzhen, Guangdong, People's Republic of China.

Less than a century ago, gastric cancer (GC) was the most common cancer throughout the world. Despite advances in surgical, chemotherapeutic, and radiotherapeutic treatment, GC remains the number 3 cancer killer worldwide. This fact highlights the need for better diagnostic biomarkers and more effective therapeutic targets. RAB11-FIP2, a member of the Rab11 family of interacting proteins, exhibits potential tumor suppressor function. However, involvement of RAB11-FIP2 in gastric carcinogenesis is yet to be elucidated. In this study, we demonstrated that RAB11-FIP2 was downregulated in GC tissues and constituted a target of the known onco-miRs, miR-192/215. We also showed that functionally, Rab11-FIP2 regulation by miR-192/215 is involved in GC-related biological activities. Finally, RAB11-FIP2 inhibition by miR-192/215 affected the establishment of cell polarity and tight junction formation in GC cells. In summary, this miR-192/215-Rab11-FIP2 axis appears to represent a new molecular mechanism underlying GC progression, while supplying a promising avenue of further research into diagnosis and therapy of GC.
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http://dx.doi.org/10.1038/s41419-018-0785-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045576PMC
July 2018

SMG-1 inhibition by miR-192/-215 causes epithelial-mesenchymal transition in gastric carcinogenesis via activation of Wnt signaling.

Cancer Med 2018 01 13;7(1):146-156. Epub 2017 Dec 13.

Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, 518060, China.

SMG-1,a member of the phosphoinositide kinase-like kinase family, functioned as a tumor suppressor gene. However, the role of SMG-1 in GC remain uncharacterized. In this study, regulation of SMG-1 by miR-192 and-215, along with the biological effects of this modulation, were studied in GC. We used gene microarrays to screening and luciferase reporter assays were to verify the potential targets of miR-192 and-215. Tissue microarrays analyses were applied to measure the levels of SMG-1 in GC tissues. Western blot assays were used to assess the signaling pathway of SMG-1 regulated by miR-192 and-215 in GC. SMG-1 was significantly downregulated in GC tissues.The proliferative and invasive properties of GC cells were decreased by inhibition of miR-192 and-215, whereas an SMG-1siRNA rescued the inhibitory effects. Finally, SMG-1 inhibition by miR-192 and-215 primed Wnt signaling and induced EMT. Wnt signaling pathway proteins were decreased markedly by inhibitors of miR-192 and-215, while SMG-1 siRNA reversed the inhibition apparently. Meanwhile, miR-192 and-215 inhitibtors increased E-cadherin expression and decreased N-cadherin and cotransfection of SMG-1 siRNA reversed these effects. In summary, these findings illustrate that SMG-1 is suppressed by miR-192 and-215 and functions as a tumor suppressor in GC by inactivating Wnt signaling and suppressing EMT.
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http://dx.doi.org/10.1002/cam4.1237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773975PMC
January 2018

MiRNA-194 activates the Wnt/β-catenin signaling pathway in gastric cancer by targeting the negative Wnt regulator, SUFU.

Cancer Lett 2017 01 31;385:117-127. Epub 2016 Oct 31.

Department of Medicine/GI Division and Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Emerging evidence has shown that miRNA-194 is aberrantly upregulated in gastric cancer (GC); however, the biological mechanisms underlying its involvement are largely unknown. Wnt/β-catenin signaling has been implicated in gastric tumorigenesis; we therefore hypothesized that miRNA-194 promotes gastric carcinogenesis by activating Wnt/β-catenin signaling. MiRNA-194 was found to be overexpressed in GC cell lines and 43 paired GC tissues. Overexpression of miRNA-194 promoted cell proliferation and migration, while inhibition of miRNA-194 blocked these processes. Inhibition of miRNA-194 decreased tumor volumes in nude mice. Furthermore, miRNA-194 inhibitors promoted cytoplasmic localization of β-catenin, leading to repression of Wnt signaling. We also discovered that SUFU, a known negative regulator of Hedgehog and Wnt signaling, was a target of miRNA-194. Anti-SUFU siRNAs rescued the inhibitory effects of miRNA-194 antagonists on cell proliferation and migration and on colony formation. We also found that SUFU expression was downregulated in GC tissues and cell lines and negatively correlated with miRNA-194 expression in primary GC tissues. Moreover, SUFU expression was negatively correlated with tumor stage, supporting its potential as a diagnostic or prognostic marker in GC. Taken together, these findings suggest that miRNA-194 is oncogenic and promotes GC cell proliferation and migration by activating Wnt signaling, at least in part, via suppression of SUFU.
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http://dx.doi.org/10.1016/j.canlet.2016.10.035DOI Listing
January 2017

The crosstalk between microRNAs and the Wnt/β-catenin signaling pathway in cancer.

Oncotarget 2017 Feb;8(8):14089-14106

Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.

Mounting evidence has indicated microRNA (miR) dysregulation and the Wnt/β-catenin signaling pathway jointly drive carcinogenesis, cancer metastasis, and drug-resistance. The current review will focus on the role of the crosstalk between miRs and the Wnt/β-catenin signaling pathway in cancer development. MiRs were found to activate or inhibit the canonical Wnt pathway at various steps. On the other hand, Wnt activation increases expression of miR by directly binding to its promoter and activating transcription. Moreover, there are mutual feedback loops between some miRs and the Wnt/β-catenin signaling pathway. Clinical trials of miR-based therapeutic agents are investigated for solid and hematological tumors, however, challenges concerning low bioavailability and possible side effects must be overcome before the final clinical application. This review will describe current understanding of miR crosstalk with the Wnt/β-catenin signaling cascade. Better understanding of the regulatory network will provide insight into miR-based therapeutic development.
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http://dx.doi.org/10.18632/oncotarget.12923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355165PMC
February 2017

Integrated miRNA profiling and bioinformatics analyses reveal potential causative miRNAs in gastric adenocarcinoma.

Oncotarget 2015 Oct;6(32):32878-89

Department of Medicine/GI Division, Johns Hopkins University and Sidney Kimmel Cancer Center, Baltimore, MD, USA.

Gastric cancer (GC) is one of the leading causes of cancer-related deaths throughout China and worldwide. The discovery of microRNAs (miRNAs) has provided a new opportunity for developing diagnostic biomarkers and effective therapeutic targets in GC. By performing microarray analyses of benign and malignant gastric epithelial cell lines (HFE145, NCI-N87, MKN28, RF1, KATO III and RF48), 16 significantly dysregulated miRNAs were found. 11 of these were validated by real-time qRT-PCR. Based on miRWalk online database scans, 703 potential mRNA targets of the 16 miRNAs were identified. Bioinformatic analyses suggested that these dysregulated miRNAs and their predicted targets were principally involved in tumor pathogenesis, MAPK signaling, and apoptosis. Finally, miRNA-gene network analyses identified miRNA-125b as a crucial miRNA in GC development. Taken together, these results develop a comprehensive expression and functional profile of differentially expressed miRNAs related to gastric oncogenesis. This profile may serve as a potential tool for biomarker and therapeutic target identification in GC patients.
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http://dx.doi.org/10.18632/oncotarget.5419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741736PMC
October 2015

Propidium iodide (PI) stains Nissl bodies and may serve as a quick marker for total neuronal cell count.

Acta Histochem 2015 Mar 14;117(2):182-7. Epub 2015 Jan 14.

School of Medicine, Shenzhen University Health Science Centre, Shenzhen University, Shenzhen, China. Electronic address:

Propidium iodide (PI) reacts with both DNA and RNA and is a commonly used fluorescent reagent for nucleic acid staining. The aim of the study was to compare the cellular staining patterns of PI with that of Nissl staining in rat nervous tissues and to report a modified staining method that selectively labels Nissl bodies in neurons. Cryosections and paraffin sections of different tissues of normal Sprague-Dawley rats, including trigeminal ganglia, dorsal root ganglia, spinal cord, liver, and small intestine, were stained by either PI or the hematoxylin and eosin method. Some sections were treated with RNase or DNase before the above staining, and some were double stained with PI and a Nissl stain. The sections were observed by light, fluorescence or confocal microscopy. Results showed strong PI signals detected as patterns of granules in the neuronal cytoplasm of all nervous tissues, whereas the staining of neuronal nuclei was weaker. In contrast, nuclei of neuroglial cells were strongly stained by PI, while the cytoplasm was not obviously stained. Pretreatment of the neural tissue with RNase abolished the PI signals. Furthermore, the PI positive granules in neuronal cytoplasm co-localized with Nissl bodies stained by the fluorescent Nissl stain. When the tissue was pretreated with DNase, PI only stained the cytoplasmic granules of neurons, but not that of glial cells. Our results show that PI stains Nissl bodies and may serve as an economical and convenient neuron marker for neuronal cell counting when specific neural markers such as antibodies are not readily available.
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http://dx.doi.org/10.1016/j.acthis.2014.12.001DOI Listing
March 2015

Temporal evolution in caveolin 1 methylation levels during human esophageal carcinogenesis.

BMC Cancer 2014 May 20;14:345. Epub 2014 May 20.

Department of Pathology, The Shenzhen University School of Medicine, 3688 Nanhai Ave, Rm 703, Nanshan, Shenzhen 518060, Guangdong, People's Republic of China.

Background: Esophageal cancer ranks eighth among frequent cancers worldwide. Our aim was to investigate whether and at which neoplastic stage promoter hypermethylation of CAV1 is involved in human esophageal carcinogenesis.

Methods: Using real-time quantitative methylation-specific PCR (qMSP), we examined CAV1 promoter hypermethylation in 260 human esophageal tissue specimens. Real-time RT-PCR and qMSP were also performed on OE33 esophageal cancer cells before and after treatment with the demethylating agent, 5-aza-2'-deoxycytidine (5-Aza-dC).

Results: CAV1 hypermethylation showed highly discriminative ROC curve profiles, clearly distinguishing esophageal adenocarcinomas (EAC) and esophageal squamous cell carcinomas (ESCC) from normal esophagus (NE) (EAC vs. NE, AUROC = 0.839 and p < 0.0001; ESCC vs. NE, AUROC = 0.920 and p < 0.0001). Both CAV1 methylation frequency and normalized methylation value (NMV) were significantly higher in Barrett's metaplasia (BE), low-grade and high-grade dysplasia occurring in BE (D), EAC, and ESCC than in NE (all p < 0.01, respectively). Meanwhile, among 41 cases with matched NE and EAC or ESCC, CAV1 NMVs in EAC and ESCC (mean = 0.273) were significantly higher than in corresponding NE (mean = 0.146; p < 0.01, Student's paired t-test). Treatment of OE33 EAC cells with 5-Aza-dC reduced CAV1 methylation and increased CAV1 mRNA expression.

Conclusions: CAV1 promoter hypermethylation is a frequent event in human esophageal carcinomas and is associated with early neoplastic progression in Barrett's esophagus.
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http://dx.doi.org/10.1186/1471-2407-14-345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035847PMC
May 2014

Aberrant methylation of the Ras-related associated with diabetes gene in human primary esophageal cancer.

Anticancer Res 2013 Nov;33(11):5199-203

The Shenzhen University School of Medicine. 3688 Nanhai Ave, Rm 703, Nanshan, Shenzhen, Guangdong, People's Republic of China 518060. Tel: +86 075586671904,

Background/aim: Ras-related associated with diabetes (RRAD), a member of the Ras-related GTPase superfamily, is frequently methylated in several human cancers, though its methylation profile remains unclear in esophageal cancer.

Materials And Methods: We examined RRAD promoter hypermethylation using real-time quantitative methylation-specific PCR in 229 primary human esophageal tissues of contrasting histological types.

Results: RRAD hypermethylation showed highly discriminative receiver-operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinoma (ESCC) from esophageal adenocarcinoma (EAC) or normal esophagus (NE) (p<0.01 and p<0.01, respectively). RRAD normalized methylation values were significantly higher in ESCC (0.0242) than in NE (0.0057, p<0.05) or EAC (0.0139, p<0.01). RRAD hypermethylation frequency was also significantly higher in ESCC (23.1%) than in NE (0%, p<0.05) or EAC (5.4%, p<0.05).

Conclusion: Promoter hypermethylation of RRAD is a frequent, tissue-specific event in ESCC, and is uncommon in EAC. The aberrant methylation of RRAD may be involved in the pathogenesis of a subset of ESCC, but not in EAC.
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November 2013

MAL hypermethylation is a tissue-specific event that correlates with MAL mRNA expression in esophageal carcinoma.

Sci Rep 2013 Oct 3;3:2838. Epub 2013 Oct 3.

1] Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China [2] Shenzhen Key Laboratory of Micromolecule Innovatal Drugs, Shenzhen, Guangdong, People's Republic of China [3] Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, People's Republic of China [4].

MAL promoter hypermethylation was examined in 260 human esophageal specimens using real-time quantitative methylation-specific PCR (qMSP). MAL hypermethylation showed highly discriminative ROC curve profiles which clearly distinguished esophageal adenocarcinomas (EAC) from both esophageal squamous cell carcinomas (ESCC) and normal esophagus (NE). Both MAL methylation frequency and normalized methylation value (NMV) were significantly higher in Barrett's esophagus (BE), dysplastic BE, and EAC than in ESCC or in NE. Among matched NE and EAC samples, MAL NMVs in EAC were significantly higher than in corresponding NE. There was a significant correlation between MAL hypermethylation and BE segment length. Treatment with 5-aza-2'-deoxycytidine reversed MAL methylation and reactivated MAL mRNA expression in OE33 EAC cells. MAL mRNA levels in EACs with unmethylated MAL were significantly higher than in EACs with methylated MAL. MAL hypermethylation is a common, tissue-specific event in human EAC and correlates with clinical neoplastic progression risk factors.
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http://dx.doi.org/10.1038/srep02838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789153PMC
October 2013

Endoglin promoter hypermethylation identifies a field defect in human primary esophageal cancer.

Cancer 2013 Oct 24;119(20):3604-9. Epub 2013 Jul 24.

Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China; Shenzhen Key Laboratory of Micromolecule Innovative Drugs, Shenzhen, Guangdong, People's Republic of China; Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, People's Republic of China.

Background: Endoglin (ENG) is a 180-kilodalton transmembrane glycoprotein that functions as a component of the transforming growth factor-β receptor complex. Recently, ENG promoter hypermethylation was reported in several human cancers.

Methods: The authors examined ENG promoter hypermethylation using real-time, quantitative, methylation-specific polymerase chain reaction in 260 human esophageal tissues.

Results: ENG hypermethylation demonstrated highly discriminative receiver operating characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) from normal esophagus (P<.01). It is interesting to note that ENG normalized methylation values were significantly higher in ESCC compared with normal tissue (P<.01) or EAC (P<.01). The ENG hypermethylation frequency was 46.2% in ESCC and 11.9% in normal esophageal tissue, but increased early and sequentially during EAC-associated neoplastic progression to 13.3% in Barrett metaplasia (BE), 25% in dysplastic BE, and 26.9% in frank EAC. ENG hypermethylation was significantly higher in normal esophageal tissue from patients with ESCC (mean, 0.0186) than in normal tissue from patients with EAC (mean, 0.0117; P<.05). Treatment of KYSE220 ESCC cells with the demethylating agent 5-aza-2'-deoxycytidine was found to reverse ENG methylation and reactivate ENG mRNA expression.

Conclusions: Promoter hypermethylation of ENG appears to be a frequent, tissue-specific event in human ESCC and exhibits a field defect with promising biomarker potential for the early detection of ESCC. In addition, ENG hypermethylation occurs in a subset of human EAC, and early during BE-associated esophageal neoplastic progression.
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http://dx.doi.org/10.1002/cncr.28276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3796027PMC
October 2013